Risks of incident major osteoporotic fractures following SARS-CoV-2 infection among older individuals: a population-based cohort study in Hong Kong.

Population-based epidemiological studies on post-acute phase coronavirus 2019 (COVID-19)-related fractures in older adults are lacking. This study aims to examine the risk of incident major osteoporotic fractures following SARS-CoV-2 infection among individuals aged ≥50, compared to individuals without COVID-19. It was a retrospective, propensity-score matched, population-based cohort study of COVID-19 patients and non-COVID individuals identified from the electronic database of the Hong Kong Hospital Authority from January 2020 to March 2022. The primary outcome was a composite of major osteoporotic fractures (hip, clinical vertebral, and upper limb). COVID-19 patients were 1:1 matched to controls using propensity-score according to age, sex, vaccination status, medical comorbidities and baseline medications. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression models. A total of 429 459 COVID-19 patients were included, 1:1 matched to non-COVID individuals. Upon median follow-up of 11 months, COVID-19 patients had higher risks of major osteoporotic fractures (5.08 vs 3.95 per 1000 persons; HR 1.22 95%CI [1.15-1.31]), hip fractures (2.71 vs 1.94; 1.33 [1.22-1.46]), clinical vertebral fractures (0.42 vs 0.31; 1.29 [1.03-1.62]), and falls (13.83 vs 10.36; 1.28 [1.23-1.33]). Subgroup analyses revealed no significant interaction. In acute (within 30 days) and post-acute phases (beyond 30 days) following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we consistently observed a significant increase in fractures and falls risks. Our study demonstrated increased risk of major osteoporotic fractures after SARS-CoV-2 infection in both acute and post-acute phases in older adults, partly due to increased fall risk. Clinicians should be aware of musculoskeletal health of COVID-19 survivors.

Our study showed that older individuals with coronavirus 2019 (COVID-19) infection are at a higher risk of suffering from major osteoporotic fractures, ie serious bone fractures related to osteoporosis, compared to those not infected. The study analyzed the health records of 429 459 patients aged 50 and older in Hong Kong who had been diagnosed with COVID-19 between January 2020 and March 2022. These patients were compared with a matched group without COVID-19, considering age, sex, vaccination status, medical comorbidities, and concomitant medications. Findings indicated that individuals who had contracted COVID-19 experienced a higher risk of major osteoporotic fractures, hip fractures, and clinical vertebral fractures. The risk of falls, a common cause of these fractures, was also higher in the COVID-19 group. This increased risk of major osteoporotic fractures and falls persists both shortly after infection and in the following months, underscoring the lasting impact of COVID-19 on the bone health of older adults. These results support the recommendations for the assessment of bone health and fall risks, and an urgent review of the requirement for interventions to reduce the risk of fragility fractures in older adult COVID-19 survivors.

Bariatric surgery, novel glucose-lowering agents, and insulin for type 2 diabetes and obesity: Bayesian network meta-analysis of randomized controlled trials.

BACKGROUND: This network meta-analysis aimed to compare the effects of bariatric surgery, novel glucose-lowering agents (SGLT2i, GLP1RA, DPP4i), and insulin for patients with type 2 diabetes mellitus (T2DM) and obesity. METHODS: Four databases were searched from inception to April 2023 to identify randomized controlled trials (RCTs) comparing bariatric surgery, SGLT2i, GLP1RA, DPP4i, insulin, and/or placebo/usual care among patients with T2DM and obesity in the achievement of HbA1c < 7.0 per cent within one year, and 12-month changes in HbA1c and body weight. RESULTS: A total of 376 eligible RCTs (149 824 patients) were analysed. Bariatric surgery had significantly higher rates of achieving HbA1c < 7.0 per cent than SGLT2i (RR = 2.46, 95 per cent c.i. = 1.28, 4.92), DPP4i (RR = 2.59, 95 per cent c.i. = 1.36, 5.13), insulin (RR = 2.27, 95 per cent c.i. = 1.18, 4.58) and placebo/usual care (RR = 4.02, 95 per cent c.i. = 2.13, 7.93), but had no statistically significant difference from GLP1RA (RR = 1.73, 95 per cent c.i. = 0.91, 3.44), regardless of oral (RR = 1.33, 95 per cent c.i. = 0.66, 2.79) or injectable (RR = 1.75, 95 per cent c.i. = 0.92, 3.45) administration. Significantly more GLP1RA patients achieved HbA1c < 7.0 per cent than other non-surgical treatments. Bariatric surgery had the greatest reductions in HbA1c (∼1 per cent more) and body weight (∼15 kg more) at 12 months. Among novel glucose-lowering medications, GLP1RA was associated with greater reductions in HbA1c than SGLT2i (-0.39 per cent, 95 per cent c.i. = -0.55, -0.22) and DPP4i (-0.51 per cent, 95 per cent c.i. = -0.64, -0.39) at 12 months, while GLP1RA (-1.74 kg, 95 per cent c.i. = -2.48, -1.01) and SGLT2i (-2.23 kg, 95 per cent c.i. = -3.07, -1.39) showed greater reductions in body weight than DPP4i at 12 months. CONCLUSION: Bariatric surgery showed superiority in glycaemic control and weight management compared to non-surgical approaches. GLP1RA administered by oral or injectable form demonstrated reduced HbA1c and body weight at 12 months, and was preferable over other non-surgical treatments among patients with T2DM and obesity. PROSPERO REGISTRATION NO: CRD42020201507.

Analysis of All-Cause Hospitalization and Death Among Nonhospitalized Patients With Type 2 Diabetes and SARS-CoV-2 Infection Treated With Molnupiravir or Nirmatrelvir-Ritonavir During the Omicron Wave in Hong Kong.

Importance: Diabetes and COVID-19 are both global pandemics, and type 2 diabetes is a common comorbidity in patients with acute COVID-19 and is proven to be a key determinant of COVID-19 prognosis. Molnupiravir and nirmatrelvir-ritonavir are oral antiviral medications recently approved for nonhospitalized patients with mild to moderate COVID-19, following demonstration of their efficacies in reducing adverse outcomes of the disease; it is crucial to clarify whether both oral antiviral medications are efficacious in a population consisting exclusively of patients with type 2 diabetes. Objective: To evaluate the effectiveness of molnupiravir and nirmatrelvir-ritonavir in a contemporary population-based cohort comprising exclusively nonhospitalized patients with type 2 diabetes and SARS-CoV-2 infection. Design, Setting, and Participants: This retrospective cohort study was performed using population-based electronic medical record data for patients in Hong Kong with type 2 diabetes and confirmed SARS-CoV-2 infection between February 26 and October 23, 2022. Each patient was followed up until death, outcome event, crossover of oral antiviral treatment, or end of the observational period (October 30, 2022), whichever came first. Outpatient oral antiviral users were divided into molnupiravir and nirmatrelvir-ritonavir treatment groups, respectively, and nontreated control participants were matched through 1:1 propensity score matching. Data analysis was performed on March 22, 2023. Exposures: Molnupiravir (800 mg twice daily for 5 days) or nirmatrelvir-ritonavir (300 mg nirmatrelvir and 100 mg ritonavir twice daily for 5 days, or 150 mg nirmatrelvir and 100 mg ritonavir for patients with an estimated glomerular filtration rate of 30-59 mL/min per 1.73 m2). Main Outcomes and Measures: The primary outcome was a composite of all-cause mortality and/or hospitalization. The secondary outcome was in-hospital disease progression. Hazard ratios (HRs) were estimated with Cox regression. Results: This study identified 22 098 patients with type 2 diabetes and COVID-19. A total of 3390 patients received molnupiravir and 2877 received nirmatrelvir-ritonavir in the community setting. After application of exclusion criteria followed by 1:1 propensity score matching, this study comprised 2 groups. One group included 921 molnupiravir users (487 men [52.9%]), with a mean (SD) age of 76.7 (10.8) years, and 921 control participants (482 men [52.3%]), with a mean (SD) age of 76.6 (11.7) years. The other group included 793 nirmatrelvir-ritonavir users (401 men [50.6%]), with a mean (SD) age of 71.7 (11.5) years, and 793 control participants (395 men [49.8%]), with a mean (SD) age of 71.9 (11.6) years. At a median follow-up of 102 days (IQR, 56-225 days), molnupiravir use was associated with a lower risk of all-cause mortality and/or hospitalization (HR, 0.71 [95% CI, 0.64-0.79]; P < .001) and in-hospital disease progression (HR, 0.49 [95% CI, 0.35-0.69]; P < .001) compared with nonuse. At a median follow-up of 85 days (IQR, 56-216 days), nirmatrelvir-ritonavir use was associated with a lower risk of all-cause mortality and/or hospitalization (HR, 0.71 [95% CI, 0.63-0.80]; P < .001) and a nonsignificantly lower risk of in-hospital disease progression (HR, 0.92 [95% CI, 0.59-1.44]; P = .73) compared with nonuse. Conclusions and Relevance: These findings suggest that both molnupiravir and nirmatrelvir-ritonavir oral antiviral medications were associated with a lower risk of all-cause mortality and hospitalization among patients with COVID-19 and type 2 diabetes. Further studies in specific populations, such as individuals in residential care homes and individuals with chronic kidney disease, are suggested.

Metformin Use in Relation to Clinical Outcomes and Hyperinflammatory Syndrome Among COVID-19 Patients With Type 2 Diabetes: A Propensity Score Analysis of a Territory-Wide Cohort.

Aim: This study was conducted in order to evaluate the association between metformin use and clinical outcomes in type 2 diabetes mellitus (T2DM) patients hospitalized with coronavirus disease 2019 (COVID-19). Methods: Patients with T2DM with confirmed diagnosis of COVID-19 and admitted between January 21, 2020, and January 31, 2021 in Hong Kong were identified in our cohort. Exposure was defined as metformin use within 90 days prior to admission until hospital discharge for COVID-19. Primary outcome was defined as clinical improvement of ≥1 point on the WHO Clinical Progression Scale (CPS). Other outcomes were hospital discharge, recovery, in-hospital death, acidosis, hyperinflammatory syndrome, length of hospitalization, and changes in WHO CPS score. Results: Metformin use was associated with greater odds of clinical improvement (OR = 2.74, p = 0.009), hospital discharge (OR = 2.26, p = 0.009), and recovery (OR = 2.54, p = 0.005), in addition to lower odds of hyperinflammatory syndrome (OR = 0.71, p = 0.021) and death (OR = 0.41, p = 0.010) than control. Patients on metformin treatment had a shorter hospital stay (-2.76 days, p = 0.017) than their control counterparts. The average WHO CPS scores were significantly lower in metformin users than non-users since day 15 (p < 0.001). However, metformin use was associated with higher odds of acidosis. Conclusions: Metformin use was associated with lower mortality and lower odds for hyperinflammatory syndrome. This provides additional insights into the potential mechanisms of the benefits of metformin use in T2DM patients with COVID-19.

Use of DPP4i reduced odds of clinical deterioration and hyperinflammatory syndrome in COVID-19 patients with type 2 diabetes: Propensity score analysis of a territory-wide cohort in Hong Kong.

BACKGROUND AND OBJECTIVES: Type 2 diabetes mellitus (T2DM) patients with Coronavirus Disease 2019 (COVID-19) have poorer prognosis. Inconclusive evidence suggested dipeptidyl peptidase-4 inhibitors (DPP4i) might reduce inflammation and prevent Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) entry, hence further evaluation on DPP4i is needed. METHODS: 1214 Patients with T2DM were admitted with COVID-19 between 21st January 2020 and 31st January 2021 in Hong Kong. Exposure was DPP4i use within the 90 days prior to admission for COVID-19. Assessed outcomes included clinical deterioration, clinical improvement, low viral load, positive Immunoglobulin G (IgG) antibody, hyperinflammatory syndrome, proportion of IgG antibody, clinical status and length of hospitalization. Multivariable logistic and linear regression models were performed to estimate odds ratios (OR) and their 95% confidence intervals (CI) of event outcomes and continuous outcomes, respectively. RESULTS: DPP4i users (N = 107) was associated with lower odds of clinical deterioration (OR=0.71, 95%CI 0.54 to 0.93, P = 0.013), hyperinflammatory syndrome (OR=0.56, 95%CI 0.45 to 0.69, P < 0.001), invasive mechanical ventilation (OR=0.30, 95%CI 0.21 to 0.42, P < 0.001), reduced length of hospitalization (-4.82 days, 95%CI -6.80 to -2.84, P < 0.001), proportion of positive IgG antibody on day-3 (13% vs 8%, p = 0.007) and day-7 (41% vs 26%, P < 0.001), despite lack of association between DPP4i use and in-hospital mortality. CONCLUSION: DPP4i use was associated with reduced odds of clinical deterioration and hyperinflammatory syndrome. Prospective studies are warranted to elucidate the role of DPP4i in T2DM and COVID-19.

Adipocyte Fatty Acid-Binding Protein, Cardiovascular Diseases and Mortality.

It has been increasingly recognized that inflammation plays an important role in the pathogenesis of cardiovascular disease (CVD). In obesity, adipose tissue inflammation, especially in the visceral fat depots, contributes to systemic inflammation and promotes the development of atherosclerosis. Adipocyte fatty acid-binding protein (AFABP), a lipid chaperone abundantly secreted from the adipocytes and macrophages, is one of the key players mediating this adipose-vascular cross-talk, in part via its interaction with c-Jun NH2-terminal kinase (JNK) and activator protein-1 (AP-1) to form a positive feedback loop, and perpetuate inflammatory responses. In mice, selective JNK inactivation in the adipose tissue significantly reduced the expression of AFABP in their adipose tissue, as well as circulating AFABP levels. Importantly, fat transplant experiments showed that adipose-specific JNK inactivation in the visceral fat was sufficient to protect mice with apoE deficiency from atherosclerosis, with the beneficial effects attenuated by the continuous infusion of recombinant AFABP, supporting the role of AFABP as the link between visceral fat inflammation and atherosclerosis. In humans, raised circulating AFABP levels are associated with incident metabolic syndrome, type 2 diabetes and CVD, as well as non-alcoholic steatohepatitis, diabetic nephropathy and adverse renal outcomes, all being conditions closely related to inflammation and enhanced CV mortality. Collectively, these clinical data have provided support to AFABP as an important adipokine linking obesity, inflammation and CVD. This review will discuss recent findings on the role of AFABP in CVD and mortality, the possible underlying mechanisms, and pharmacological inhibition of AFABP as a potential strategy to combat CVD.

Management of Familial Hypercholesterolemia: Current Status and Future Perspectives.

Familial hypercholesterolemia (FH) is the most common monogenic disorder associated with premature atherosclerotic cardiovascular disease. Early diagnosis and effective treatment can significantly improve prognosis. Recent advances in the field of lipid metabolism have shed light on the molecular defects in FH and new therapeutic options have emerged. A search of PubMed database up to March 2020 was performed for this review using the following keywords: "familial hypercholesterolemia," "diagnosis," "management," "guideline," "consensus," "genetics," "screening," "lipid lowering agents." The prevalence rate of heterozygous FH is approximately 1 in 200 to 250 and FH is underdiagnosed and undertreated in many parts of the world. Diagnostic criteria have been developed to aid the clinical diagnosis of FH. Genetic testing is now available but not widely used. Cascade screening is recommended to identify affected family members, and the benefits of early interventions are clear. Treatment strategy and target is currently based on low-density lipoprotein (LDL) cholesterol levels as the prognosis of FH largely depends on the magnitude of LDL cholesterol-lowering that can be achieved by lipid-lowering therapies. Statins with or without ezetimibe are the mainstay of treatment and are cost-effective. Addition of newer medications like PCSK9 inhibitors is able to further lower LDL cholesterol levels substantially, but the cost is high. Lipoprotein apheresis is indicated in homozygous FH or severe heterozygous FH patients with inadequate response to cholesterol-lowering therapies. In conclusion, FH is a common, treatable genetic disorder, and although our understanding of this disease has improved, many challenges still remain for its optimal management.

Development of a Non-Invasive Liver Fibrosis Score Based on Transient Elastography for Risk Stratification in Patients with Type 2 Diabetes.

BACKGROUND: In non-alcoholic fatty liver disease (NAFLD), transient elastography (TE) is an accurate non-invasive method to identify patients at risk of advanced fibrosis (AF). We developed a diabetes-specific, non-invasive liver fibrosis score based on TE to facilitate AF risk stratification, especially for use in diabetes clinics where TE is not readily available. METHODS: Seven hundred sixty-six adults with type 2 diabetes and NAFLD were recruited and randomly divided into a training set (n=534) for the development of diabetes fibrosis score (DFS), and a testing set (n=232) for internal validation. DFS identified patients with AF on TE, defined as liver stiffness (LS) ≥9.6 kPa, based on a clinical model comprising significant determinants of LS with the lowest Akaike information criteria. The performance of DFS was compared with conventional liver fibrosis scores (NFS, FIB-4, and APRI), using area under the receiver operating characteristic curve (AUROC), sensitivity, specificity, positive and negative predictive values (NPV). RESULTS: DFS comprised body mass index, platelet, aspartate aminotransferase, high-density lipoprotein cholesterol, and albuminuria, five routine measurements in standard diabetes care. Derived low and high DFS cut-offs were 0.1 and 0.3, with 90% sensitivity and 90% specificity, respectively. Both cut-offs provided better NPVs of >90% than conventional fibrosis scores. The AUROC of DFS for AF on TE was also higher (P<0.01) than the conventional fibrosis scores, being 0.85 and 0.81 in the training and testing sets, respectively. CONCLUSION: Compared to conventional fibrosis scores, DFS, with a high NPV, more accurately identified diabetes patients at-risk of AF, who need further evaluation by hepatologists.

Carbamylated HDL and Mortality Outcomes in Type 2 Diabetes.

OBJECTIVE: Carbamylation is part of the aging process and causes adverse changes in the structure and function of proteins. Lipoproteins are subjected to carbamylation. We investigated the usefulness of carbamylated HDL as a prognostic indicator of survival in patients with type 2 diabetes and the association with mortality outcomes. RESEARCH DESIGN AND METHODS: Baseline plasma carbamylated HDL was measured by ELISA in a cohort of 1,517 patients with type 2 diabetes. The primary outcome was all-cause mortality, and the secondary outcomes were cause-specific deaths, including cardiovascular, renal, infection, and cancer related. RESULTS: Over a median follow-up of 14 years, 292 patients died, and the mortality rate was 14.5 per 1,000 person-years. Plasma carbamylated HDL level was higher in those with a fatal outcome (46.1 ± 17.8 µg/mL vs. 32.9 ± 10.7; P < 0.01). Patients in the third (hazard ratio [HR] 2.11; 95% CI 1.40-3.17; P < 0.001) and fourth quartiles (HR 6.55; 95% CI 4.67-9.77; P < 0.001) of carbamylated HDL had increased mortality risk. After adjustment for conventional risk factors, elevated carbamylated HDL was independently associated with all-cause mortality (HR 1.39; 95% CI 1.28-1.52; P < 0.001) as well as with all the cause-specific mortalities. Adding plasma carbamylated HDL level improved the power of the multivariable models for predicting all-cause mortality, with significant increments in C index (from 0.78 to 0.80; P < 0.001), net reclassification index, and integrated discrimination improvement. CONCLUSIONS: Carbamylation of HDL renders HDL dysfunctional, and carbamylated HDL is independently associated with mortality outcomes in patients with type 2 diabetes.

Different glycaemia-related risk factors for incident Alzheimer's disease in men and women with type 2 diabetes-A sex-specific analysis of the Hong Kong diabetes database.

AIMS: Sexual dimorphism has been reported in the epidemiology, neurobiologic susceptibility and clinical presentation of Alzheimer's disease (AD). As poor glycaemic control is associated with increased risks of AD, we aimed to investigate whether glycaemia-related risk factors also differ between men and women, using a retrospective, sex-specific analysis of a large Chinese cohort with diabetes. MATERIALS & METHODS: A total of 85,514 Chinese individuals with type 2 diabetes (T2D; 46,783 women and 38,731 men), aged ≥60 years, were identified from electronic health records and observed for incident AD. Multivariable Cox regression analysis was used to evaluate the associations with incident AD of several glycaemia-related risk factors, including severe hypoglycaemia, mean HbA1c and indices of HbA1c variability, in men and women separately. RESULTS: Over a median follow-up of 6 years, women had a higher incidence of AD than men (2.3% vs. 1.2%, p < 0.001). Both men and women shared the same independent non-glycaemic clinical predictors, which included older age, lower body mass index and longer duration of diabetes. However, for glycaemia-related risk factors, we observed that severe hypoglycaemia and indices of HbA1c variability were independent predictors of incident AD in women but not in men, and the associations were irrespective of their baseline glycaemic control and duration of diabetes. CONCLUSIONS: Our findings highlighted that glycaemia-related risk factors for incident AD differ between men and women with T2D. Strategies to maintain glycaemic stability and avoid severe hypoglycaemia might be especially important to preserve healthy cognition in older women with diabetes.

Higher Circulating Adiponectin Concentrations Predict Incident Cancer in Type 2 Diabetes - The Adiponectin Paradox.

INTRODUCTION: Despite the beneficial cardiometabolic effects of adiponectin demonstrated in preclinical studies, paradoxically higher circulating adiponectin concentrations have been found in epidemiological studies to be associated with incident cardiovascular events, renal outcomes, and mortality in patients with diabetes. On the other hand, diabetes is also associated with an increased risk of cancer. Here, we investigated prospectively the association between circulating adiponectin concentrations and incident cancer using a cohort of exclusively individuals with type 2 diabetes. MATERIALS AND METHODS: Baseline serum adiponectin concentrations were measured in 5658 participants recruited from the Hong Kong West Diabetes Registry. The associations of circulating adiponectin concentrations with incident cancer and cancer-related deaths were evaluated using multivariable Cox regression analysis, with hazard ratio (HR) for adiponectin referring to the respective risk per doubling of serum adiponectin concentration. RESULTS: Over a median-follow up of 6.5 years, 7.53% and 3% of participants developed cancer and had cancer-related deaths, respectively. Serum adiponectin concentrations were significantly higher in those who had incident cancer (9.8 µg/mL vs 9.1 µg/mL, P < 0.001) and cancer-related deaths (11.5 µg/mL vs 9.3 µg/mL, P < 0.001) compared with those without. Moreover, in multivariable analyses, serum adiponectin concentration was independently associated with both incident cancer (hazard ratio, 1.19; 95% confidence interval, 1.05-1.35; P = 0.006) and cancer-related deaths (hazard ratio, 1.23; 95% confidence interval, 1.03-1.47; P = 0.024). CONCLUSIONS: Higher serum adiponectin concentration was independently associated with incident cancer and cancer-related deaths in type 2 diabetes, indicating that adiponectin paradox can be observed in another major diabetic complication in addition to cardiovascular and kidney diseases.

A young Chinese man with nephrotic syndrome due to lipoprotein glomerulopathy.

Lipoprotein glomerulopathy (LPG) is a rare autosomal dominant renal disease with incomplete penetrance, associated with specific protein-modifying mutations in the APOE gene. LPG is associated with poor renal prognosis, in which lipoprotein thrombi are seen in the glomerular capillaries. Dyslipidemia in LPG generally resembles type III hyperlipoproteinemia with elevated serum apolipoprotein E level. Fibrate is the most frequently reported lipid-lowering therapy in LPG as hypertriglyceridemia is common in these individuals. There are few existing case reports on effectiveness of statin monotherapy for LPG. We report a 32-year-old Chinese man who presented with nephrotic syndrome, renal impairment, severe hypercholesterolemia without hypertriglyceridemia, and hypertension. Renal biopsy confirmed lipoprotein glomerulopathy. Genetic testing confirmed APOE Kyoto mutation. Anti-hypertensive therapy, including angiotensin receptor blocker, and statin were initiated. Concomitant with normalization of lipid profile, his proteinuria markedly improved, and his renal function has remained stable up to 3 years, demonstrating sustained benefit with statin monotherapy in LPG.

Prospective associations of circulating adipocyte fatty acid-binding protein levels with risks of renal outcomes and mortality in type 2 diabetes.

AIMS/HYPOTHESIS: Elevated circulating adipocyte fatty acid-binding protein (AFABP) levels have been found to correlate with diabetic nephropathy staging in cross-sectional studies. However, it remains unclear whether these higher serum levels reflect a role of AFABP in the development of diabetic kidney disease (DKD), or simply result from its impaired renal clearance in DKD. Here we investigated prospectively the prognostic importance of serum AFABP level in the development of adverse renal outcomes in a large clinic-based cohort of participants with type 2 diabetes. METHODS: Baseline serum AFABP levels were measured in 5454 Chinese participants from the Hong Kong West Diabetes Registry. The association between circulating AFABP levels and incident adverse renal outcomes-defined as a composite endpoint of a sustained 40% decline in eGFR, end-stage renal disease requiring renal replacement therapy or kidney transplantation, or renal deaths-was evaluated using multivariable Cox regression analysis. RESULTS: Over a median follow-up of 5 years, 754 of the 5454 participants developed incident adverse renal outcomes. Elevated circulating AFABP levels were independently associated with incident adverse renal outcomes (HR 1.43, 95% CI 1.31, 1.57, p < 0.001) after adjustments for conventional risk factors for DKD progression. Importantly, the prognostic role of serum AFABP was independent of the baseline albuminuria status or eGFR levels of the study participants. CONCLUSIONS/INTERPRETATION: Circulating AFABP levels were predictive of incident adverse renal outcomes, even in participants with relatively well-preserved kidney function at baseline, suggesting its potential to be a useful marker for early risk stratification in DKD.

Circulating Adipocyte Fatty Acid-Binding Protein Concentrations Predict Multiple Mortality Outcomes among Men and Women with Diabetes.

INTRODUCTION: Raised circulating adipocyte fatty acid-binding protein (AFABP) concentrations are associated with various adverse health conditions. However, their relationship with mortality remains to be defined, especially in view of the sexual dimorphism of circulating AFABP concentrations. Here we investigated prospectively whether serum AFABP concentrations predict multiple mortality outcomes in men and women alike, using a large clinic-based cohort of individuals with type 2 diabetes, a condition with raised AFABP concentrations. METHODS: Baseline serum AFABP concentrations were measured in 5305 research participants with a monoclonal antibody-based sandwich immunoassay. The role of circulating AFABP concentrations in predicting mortality outcomes was evaluated by multivariable Cox regression analysis. RESULTS: Among the 5305 participants (59% men) in this study, over a median follow-up of 5 years, there were 512 deaths (19.3 deaths per 1000 person-years). Circulating AFABP concentrations, with higher levels in women at baseline, predicted all-cause mortality (P < 0.001), cardiovascular mortality (P = 0.037), and infection-related deaths (P < 0.002) among all participants. In sex-specific analyses, circulating AFABP concentration was an independent predictor of all-cause mortality in both men and women and a predictor of cancer-related deaths and infection-related deaths in men only. Furthermore, the addition of serum AFABP concentrations improved the time-dependent c statistics in predicting all-cause mortality in participants with type 2 diabetes (P = 0.008). CONCLUSIONS: Circulating AFABP concentration was an independent predictor of various mortality outcomes in type 2 diabetes over and above known risk factors of reduced survival in men and women. The role of AFABP as a prognostic biomarker and therapeutic target warrants further investigation.